Desórdenes congénitos de la glicosilación (CDG): búsqueda de variantes génicas y alteraciones glicoproteicas en pacientes argentinos.
Parole chiave:
tesis doctorales, bioquímica, glicoproteínas, enfermedades genéticas, biosíntesis, desórdenes genéticos, diagnóstico de laboratorioAbstract
Los Desórdenes Congénitos de Glicosilación (CDG) son enfermedades genéticas humanas causadas por defectos en la síntesis de N-, O-glicoproteínas o en la síntesis de glicolípidos. Existen distintos tipos de CDG que abarcan defectos en la biosíntesis de azucarares-nucleótidos, transportadores, glicosiltransferasas, transporte vesicular, como también en la biosíntesis de lípidos y anclajes de glicosilfosfatidilinositol (GPI). Las manifestaciones clínicas son muy variadas, se presentan con fenotipos multisistémicos leves, o incluso graves, afectando la mayoría de los órganos y sistemas. Las formas más severas se asocian a alteraciones neurológicas que van desde el retraso psicomotor grave a moderada discapacidad intelectual. Los eventos trombohemorrágicos son muy frecuentes, siendo en gran medida causados por alteraciones de agregación plaquetaria. Este espectro fenotípico tan amplio, hace que el diagnóstico sea dificultoso en la mayoría de los casos. En este trabajo de tesis se ha combinado el uso de diferentes tecnologías no implementadas hasta el momento en nuestro país para el diagnóstico de CDG. De esta manera se agilizó el protocolo diagnóstico con aumento de la tasa de éxito en la caracterización de pacientes. La utilización de secuenciación masiva de genes (NGS) en sus diferentes algoritmos (secuenciación del exoma completo, secuenciación de un panel de genes), en combinación con secuenciación Sanger y estudios bioquímicos convencionales (IEF-Tf) nos ha permitido identificar tres pacientes PMM2-CDG,un paciente COG1-CDGy tres pacientes ALG2-CDG, los primeros con una variante en homocigosis no reportada hasta el momento. También se pudo detectar alteraciones secundarias de la glicosilación de transferrina, no asociadas a CDG, llegando a diagnosticar un paciente con mutaciones en el gen DYRK1A. La combinación de NGS trae aparejada la identificación de nuevos genes o bien de variantes clínicas de significado incierto (VUS) en genes ya descritos para CDG, haciendo imperiosa la necesidad de caracterizar y validar estos nuevos cambios detectados. Las herramientas de análisis glicómico incorporadas nos permitieron caracterizar el perfil glicómico de pacientes ALG2-CDG, tanto en glicoproteínas totales de suero como asociado específicamente a Tf, estudios fundamentales para describir este tipo de CDG y defecto de glicosilación que ocasiona este gen mutado en la vía de formación de Nglicanos. La caracterización del perfil glicómico plaquetario en PMM2-CDG permitió xi aportar conocimiento respecto a mecanismos fisiopatogénicos asociados a la hipoglicosilación en pacientes CDG. Los resultados de esta tesis, en conjunto, destacan la utilidad de la NGS y la implementación de herramientas glicómicas, para ser aplicada al diagnóstico y caracterización de pacientes CDGs, el diagnóstico genético preciso necesario para proporcionar asesoramiento genético, prescribir tratamientos personalizados y proporcionar conocimientos para orientar la investigación hacia la búsqueda de nuevas terapias en el campo de la Medicina Personalizada o Medicina de Precisión.Downloads
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